Many human disorders of central nervous system (CNS) development have an important genetic component, but the underlying genetic defects are often unknown. Such disorders fall into two groups: 1) rare autosomal recessive disorders with insufficient family material or with genetic heterogeneity that confounds linkage analysis, and 2) more common genetic disorders but which have complex patterns of inheritance. Most such disorders have not been observed occurring spontaneously in laboratory mouse populations, and lacking the identity of the causative gene or genes, it is not possible to create mouse knockout models by targeted gene disruption. However, dogs are a rich source of accurate and naturally occurring animal models of human genetic disease that can be used for the discovery of underlying genetic causes. Recently, we have observed a large pedigree of dogs in which fetal arrest of brain and spinal cord development occurs as a simple autosomal recessive trait and produces a lethal clinical phenotype that closely models pontocerebellar hypoplasia type I (PCH I) of humans. PCH I is a neurodegenerative disorder of the developing central nervous system affecting the brainstem, cerebellum, and motor neurons of the spinal cord, but phenotypic expression of the disease varies, even within families. This heterogeneity and a paucity of PCH I pedigrees for use in linkage analysis and positional cloning make it difficult to determine the genetic basis of the disorder. We propose to take a genetic approach for the identification of the gene responsible for this canine model of an inherited CNS developmental disorder. This approach is now feasible using recently available canine linkage and radiation hybrid maps and other new high-resolution genetic resources for comparative positional-candidate cloning of disease genes. The aims of this project are to use linkage analysis, combined with detailed description of the progression and pathology of the canine disorder, to determine the underlying gene defect. In addition to identifying the primary defect that underlies the neurodevelopmental abnormality, these studies will improve understanding of a pathogenesis that is common to a heterogeneous group of human disorders and provide a well-characterized large animal model for potential development of treatments for pediatric disorders of this type.